BACKGROUND: Antidepressant-induced sexual dysfunction affects approximately 50% of patients taking antidepressants. Previous research has explored sildenafil’s effectiveness in treating various forms of erectile dysfunction, but there is no research supporting sildenafil’s use for improving the quality of life for patients with sexual dysfunction linked to antidepressant use. The authors of this article aimed to assess the improvements in quality of life in patients taking sildenafil to treat antidepressant-induced sexual dysfunction.

METHODS: One hundred and two out of 2,239 male and female patients in the follow-up phase of the Sequenced Treatment Alternatives to Relieve Depression antidepressant trials who complained of sexual dysfunction were given sildenafil, 50 to 100 mg, as needed. After 12 months, we measured patients’ change in libido, sexual drive, family relationships, overall well-being, satisfaction with treatment, and overall contentment with items on the 17-item Hamilton Depression Rating Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, 30-item Inventory of Depressive Symptoms, and 12-item Short Form Health Survey.

RESULTS: There was a significant association between sildenafil use and improvement in libido and sexual drive by month 6. There was no significant improvement in the quality-of-life scores we examined, but treatment satisfaction and overall contentment increased over time.

CONCLUSIONS: Despite no direct association with sildenafil use and quality-of-life scores, sildenafil may be a beneficial treatment for antidepressant-induced sexual dysfunction. A double-blind, placebo-controlled study of sildenafil in antidepressant-induced sexual dysfunction is needed to further explore its potential benefits.

INTRODUCTION

Antidepressant-induced sexual dysfunction is a significant issue in the treatment of patients with mood disorders, affecting about 50% of patients who receive antidepressant treatment.1 Patients with antidepressant-induced sexual dysfunction report that changes in sexual function negatively affect their self-esteem, mood, and relationships with their sexual partners.1 The sexual dysfunction associated with the use of antidepressants may be so distressing to some patients that they prematurely self-discontinue their antidepressant treatment despite adequate improvement in their depressive symptoms.2 Given the importance of normal sexual functioning in the lives of patients, effective treatment for antidepressant-associated sexual dysfunction is vital. Accordingly, we anticipate that an effective form of treatment for this common side effect would improve patients’ quality of life.

Sildenafil has been established as the standard of care for male erectile dysfunction.3 To further explore other uses of sildenafil, we examined the results of a large antidepressant study, Sequenced Treatment Alternatives to Relieve Depression (STAR*D), in which both male and female responders to antidepressant treatment who complained clinically of sexual dysfunction while taking antidepressants were prescribed sildenafil, 50 to 100 mg, as needed, during a 1-year follow-up to an acute antidepressant treatment period. In this report, we examine the results of this course of treatment with sildenafil. We hypothesized that antidepressant responders or remitters who complained of sexual dysfunction and received sildenafil (50 to 100 mg/d) would demonstrate a statistically significant improvement in scale items measuring sexual dysfunction from the 30-item Inventory of Depressive Symptoms (IDS-C30) (item 22 – sexual interest),4 from the 17-item Hamilton Depression Rating Scale (HDRS17) (item 14 – libido),5 and from the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) (item 9 – sexual drive).

As a secondary hypothesis, we predicted that sildenafil use would be associated with a statistically significant improvement in quality of life, as measured by the Q-LES-Q items 6 (familial relationships), 14 (overall well-being), 15 (satisfaction with treatment), and 16 (overall contentment).6 Finally, we predicted that improvement in sexual function would be associated with improvement in the overall Q-LES-Q score, and with improvement in the Physical and Mental health summary measures of the 12-item Short Form Health Survey (SF-12).7

METHODS

The present work is a post hoc analysis of data from STAR*D, a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depression who did not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant.8 The STAR*D study was conducted in accordance with the Declaration of Helsinki, Fifth Revision (2002-2004). The study design was approved by each participating site’s ethical committee(s) and all participants gave informed consent after fully understanding the study procedures. The study enrolled 4,041 adults (age 18 to 75), from both primary and specialty care practices, who had neither a prior inadequate response nor clear-cut intolerance to a robust trial of protocol treatments during their current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit were eligible for randomization to level 2 treatments, which entailed 4 switching options (sertraline, bupropion, venlafaxine, or cognitive therapy) and 3 citalopram augmentation options (bupropion, buspirone, or cognitive therapy). Those who received cognitive therapy (switching or augmentation options) at level 2 without sufficient improvement were eligible for randomization to 1 of 2 level 2A switching options (venlafaxine or bupropion). Level 2 and 2A participants without sufficient improvement were eligible for random assignment to 2 switching options (mirtazapine or nortriptyline) and to 2 augmentation options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 were eligible for level 4 random assignment to 1 of 2 switching options (tranylcypromine or the combination of mirtazapine and venlafaxine). Participants with an adequate symptomatic response at the end of any of these levels then had the opportunity to enter a 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments, during which time they would continue their antidepressant treatment. Treatment responders who complained of sexual dysfunction during this naturalistic follow-up period were offered treatment with open-label sildenafil with a starting dose of 50 mg/d, increased up to 100 mg as needed. For the purpose of this article, those participants who entered the naturalistic follow-up from level 1 will be examined.

In order to examine the effect of sildenafil on sexual functioning and quality of life, we analyzed items from several standardized scales. Scales included the HDRS17, IDS-C30, and Q-LES-Q, which were administered at pretreatment, at exit from each treatment level, and at months 3, 6, 9, and 12 of follow-up. End points in this investigation were defined as the last study visit at which sildenafil was prescribed during the 12-month follow-up period. The primary tests of outcome were the degree of changes in item 14 (libido) of the HDRS17 scale, item 9 (sexual drive) of the Q-LES-Q, and item 22 (libido) of the IDS-C30.

Secondary outcome measures to assess quality of life included changes in items 6 (familial relationships), 14 (overall well-being), 15 (satisfaction with treatment), and 16 (overall contentment) of the Q-LES-Q, as well as the change in total score on the Q-LES-Q and the SF-12 physical and mental summary scores.7

All patients prescribed sildenafil in the follow-up phase with at least 1 follow-up visit were compared with those who were not prescribed sildenafil. Mixed-model regression was used to determine the association between sildenafil use and changes in the HDRS17 and Q-LES-Q items of interest, as well as the change in these items over time and the interaction between treatment and time. The relationship between change in sexual functioning and the total change in Q-LES-Q score, SF-12 physical summary score, and SF-12 mental summary score, and their respective associations with time and sex, was similarly assessed. A 2-tailed alpha level of .05 was set for all statistical tests.

RESULTS

A total of 2,239 participants (62.4% female; mean age, 41.4 ± 13.2 years) entered the follow-up phase of treatment. Of the 2,239 patients in follow-up for whom sildenafil status was available, 102 (4.6%) took sildenafil; of these patients, 68.6% were male; 79.4% were white; 23.5% were age 18 to 30; 45.1% were age 31 to 50; and 31.4 % were age ≥51. Patient demographics and depression severity scores are detailed in TABLE 1.

We observed gradual improvement in libido and sexual functioning over time in patients receiving sildenafil (TABLE 2), and there was a significant association between use of sildenafil and improvement in the HDRS17 libido item 14 (P = .0002) and the IDS-C30 sexual interest item 22 (P = .0004) (TABLE 3). Improvement in HDRS17 item 14 (libido) and IDS-C30 item 22 (sexual functioning) peaked at 6 months of follow-up, with some reversion at months 9 and 12, although final scores were still improved over baseline (TABLE 2). The improvement was thus not found to be time dependent (TABLE 3). Of interest, there was no improvement at all in HDRS17 item 14 (libido) and IDS-C30 item 22 (sexual functioning) among patients who were not prescribed sildenafil, although there was some improvement in sexual drive on the Q-LES-Q (TABLE 4). Q-LES-Q item 9 (sexual drive) improved more steadily over the 12-month follow-up period (TABLE 2) for those prescribed sildenafil as well; however, the improvement was significantly associated with time (P = .0269) but not sildenafil use (P = .4628) (TABLE 3).

Use of sildenafil was not associated with significant improvement on the selected quality-of-life items of the Q-LES-Q (TABLE 3), although there was a significant time-related improvement in overall contentment (P = .0081), which remained significant after interaction with sildenafil treatment. There was a significant association between change in sexual functioning and quality of life, based on overall change in Q-LES-Q (TABLE 5). As sexual function worsened, quality of life decreased, independent of sex (TABLE 5). Improvement in the mental health summary score of the SF-12 was significantly associated with increased sexual function (P < .0001) but not with time or sex (TABLE 5). Improvement in the physical health summary score of the SF-12 had a significant association with time only (P < .0001) (TABLE 5).

TABLE 5

Association of change in sexual function with quality of life and functioning

DISCUSSION

Although sildenafil has been shown to improve male erectile and orgasmic dysfunction associated with the use of antidepressants,3 it has not previously been shown to be statistically significantly superior to placebo for treating deficits in libido. It is therefore of interest that in our sample, sildenafil use was associated with significant improvement on the HDRS17 and IDS-C30 items that focus exclusively on desire or libido. As we did not investigate the underlying etiology of sexual dysfunction (eg, residual symptoms of depression, antidepressant induced, or other medical or psychological causes), it is possible that libido as a residual symptom of depression responds more slowly to antidepressant treatment and thus improved with the passage of time rather than as a result of sildenafil use during the follow-up period. However, given the general lack of association between improvement in sexual functioning and time (TABLE 4), this explanation seems unlikely.

The observed dampening of initial improvement, noted at months 9 and 12 with regard to the HDRS17 libido item and the IDS-C30 sexual functioning item (TABLE 2), is intriguing, particularly when contrasted with the continued improvement on most of the Q-LES-Q measures, including its sexual drive item (TABLE 2). It is possible that patients may have stopped taking the sildenafil, or used it less consistently than in the first 6 months of the follow-up period. This would explain a less robust improvement in libido, although quality of life overall may have continued to improve as a function of continued depressive remission. Overall, these findings, along with those of a previous study showing significant improvement in libido among subjects with antidepressant-induced sexual dysfunction who took maca root,9 suggest that libido may be traceable to agents that improve general sexual functioning. Further investigation into this aspect of sexual dysfunction management is warranted.

In our study, sildenafil was not associated with improvement in specific quality-of-life measures (TABLE 4), although improvements in sexual functioning were associated with improvement in overall quality of life per the Q-LES-Q and the SF-12 mental health summary measure (TABLE 5). In previous studies, the use of sildenafil was clearly associated with improvement in quality of life in males with erectile dysfunction,10 and particularly in males with erectile dysfunction and end-stage renal disease,11 comorbid hypertension, hyperlipidemia, benign prostatic hyperplasia, and depression.12 Because we measured only libido and not erectile dysfunction, it is possible that the direct association between the use of sildenafil and improvement in quality of life went undetected, especially if prior associations were based primarily on improved erectile function. However, the association between improvement in sexual functioning and quality of life was significant in both sexes, suggesting that both men and women with remitted depression may experience improvements in overall quality of life if their sexual dysfunction is treated aggressively.

The study is limited by a relatively small sample of sildenafil users and by the lack of a comparison group, because presumably only the patients who were prescribed sildenafil had reported sexual dysfunction. Those patients prescribed sildenafil had complained of sexual dysfunction; we do not have data to know what proportion of those not prescribed sildenafil may also have been experiencing sexual dysfunction. We did not have compliance data available to determine whether all patients who were prescribed sildenafil took it consistently and as directed, although the generally positive findings would suggest that compliance was good. As mentioned, inquiry about erectile function per se in males would have given a more complete picture of the overall impact of sildenafil in the sample. Finally, this is an examination of association, which does not prove a direct causality of improvement in quality of life secondary to improvement in libido or sexual function. Prospective studies are needed to answer this question more conclusively.

CONCLUSIONS

It appears that sildenafil therapy may have beneficial effects on libido and overall quality of life in men and women with major depressive disorder in remission who have residual sexual dysfunction. Further characterization of the effects of sildenafil in depressed populations appears warranted.

The initial STAR*D project was supported with federal funds from the NIMH/National Institutes of Health under contract N01MH90003 to the University of Texas Southwestern Medical Center, Dallas (PI: Dr. A.J. Rush). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. The NIMH approved the design of the overall study and reviewed its conduct but performed no role in the collection, management, or interpretation of the data analyzed for this report or in the preparation, review, or approval of the manuscript. We appreciate the support of Bristol-Myers Squibb, Forest Laboratories, GlaxoSmithKline, King Pharmaceuticals, Organon, Pfizer, Inc., and Wyeth for providing medications at no cost for the original STAR*D trial. None of these entities had a role in any part of the study (eg, design, execution, data collection, analysis, or interpretation of the data), nor in writing any report, including this one.